Cholesterol Metabolism

Cholesterol Metabolism

• Cholesterol is a crucial steroid alcohol found in animal tissues.
• It's a structural component of all cell membranes, influencing membrane fluidity.
• Cholesterol is a precursor for bile acids, steroid hormones, and vitamin D.
• The liver plays a central role in cholesterol homeostasis.
• Cholesterol enters the liver from dietary sources and de novo synthesis by non-liver tissues and the liver.
• Cholesterol exits the liver as unmodified cholesterol in bile or is converted into bile salts, secreted into the intestinal lumen.
• Cholesterol also contributes to plasma lipoproteins directed to peripheral tissues.
• In humans, cholesterol influx and efflux are not perfectly balanced, leading to gradual cholesterol deposition, primarily in the endothelial linings of blood vessels.
• Lipid deposition causes plaque formation and blood vessel narrowing (atherosclerosis). This raises the risk of heart, brain, and peripheral vascular diseases.
• Cholesterol synthesis sites include liver, adrenal cortex, testes, ovaries, and intestine.
• All nucleated cells can synthesize cholesterol, including arterial walls.
• Cholesterol synthesis enzymes exist in both endoplasmic reticulum and cytoplasm.

Bile Acids and Bile Salts

• Bile is a watery mixture of organic and inorganic compounds.
• Phosphatidylcholine (lecithin) and bile salts (conjugated bile acids) are the primary organic components.
• Bile can either flow directly from the liver into the duodenum through the common bile duct, or be stored in the gallbladder until needed for digestion.
• Intestine bacteria remove glycine and taurine from bile salts, regenerating bile acids.
• Bacteria also convert primary bile acids to secondary bile acids (by removing a hydroxyl group). For example, deoxycholic acid is derived from cholic acid.

Bile Salt Deficiency

• Bile salt deficiency leads to cholesterol gallstones, called cholelithiasis.
• Cholesterol precipitates in the gallbladder due to decreased bile salt levels, or increased cholesterol.
• Low bile acid and elevated cholesterol levels can cause gallstone formation.

Regulation of Cholesterol

• HMG CoA reductase is a key regulatory enzyme for cholesterol synthesis.
• Insulin and thyroid hormone increase HMG CoA reductase activity.
• Cortisol and glucagon decrease this enzyme's activity.
• Lovastatin and similar "statin" drugs inhibit HMG CoA reductase competitively to lower cholesterol levels.

Cholesterol Absorption and Excretion

• Dietary fiber binds bile acids and increases their excretion, resulting in reduced bile acid recycling and consequently reduced cholesterol synthesis.
• Gross malabsorption of bile acids in the intestine (especially in patients with severe ileal disease), biliary tract obstruction, and/or severe hepatic dysfunction (affects bile salt production), can also cause cholelithiasis.
• Elevated biliary cholesterol excretion (such as with fibrate use) can also result in cholelithiasis.

Treatment Options

• Laparoscopic cholecystectomy (removing the gallbladder) is the typical treatment.
• Oral chenodeoxycholic acid can dissolve gallstones for those who can't undergo surgery, but this takes months or years.